The long-term objective of this proposal is to gain insight into vitamin D-dependent mechanisms of innate and adaptive immunity in humans. Our previous work has revealed a new immunologic paradigm which underscores the importance of adequate circulating 25-hydroxyvitamin D (25D) levels for human host defense against microbial infection. We demonstrated that in human macrophages: innate and adaptive mechanisms activate different receptors but converge on a common vitamin D receptor (VDR)-driven antimicrobial pathway against M. tuberculosis (mTB) involving the induction of IL-15 and the the vitamin D-1-hydroxylase (CYP27b1), which converts 25D to the active metabolite 1,25-dihydroxyvitamin D (1,25D). Subsequent activation of the VDR induces downstream genes coding for the antimicrobial peptides cathelicidin and DEFB4, together with induction of autophagy, result in antimicrobial activity. Strikingly, this antimicrobial pathway was dependent on levels of 25D, which also correlate with susceptibility to tuberculosis in humans. Our central hypothesis is that adequate circulating 25D levels are critically required for effective innate and adaptive immune responses against mTB, which we will test according to the following specific aims: 1) define the distinct and interactive roles of IL-15 and IL-32 in the induction of the 25D-dependent antimicrobial pathway, 2) investigate counter-regulation of antimicrobial activity by Type I IFNs; and 3) determine the effects of 25D availability on dendritic cell (DC) function. The proposed studies will provide new information about the mechanisms of human innate and adaptive immunity with specific relevance to TB but of significance to the potential use of simple, inexpensive vitamin D supplementation as an adjunct to prevention and therapy of infectious disease.